Multipeptide-coupled nanoparticles induce tolerance in ‘humanised’ HLA-transgenic mice and inhibit diabetogenic CD8+ T cell responses in type 1 diabetes
Multipeptide-coupled nanoparticles induce tolerance in ‘humanised’ HLA-transgenic mice and inhibit diabetogenic CD8+ T cell responses in type 1 diabetes
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多肽偶联纳米粒子诱导“人源化”HLA 转基因小鼠的耐受性并抑制 1 型糖尿病中致糖尿病的 CD8 T 细胞反应
DOI：
10.1007/s00125-017-4419-8
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发表时间：
2017-09
期刊：
影响因子：
8.2
通讯作者：
Yang Tao
中科院分区：
文献类型：
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作者：
Yang Tao
目的/假设：抗原特异性免疫耐受的诱导可能在 NOD 小鼠模型中提供一种有吸引力的免疫疗法，但导致成功转化为人类 1 型糖尿病的条件有限。在这项研究中，我们将 500 nm 羧化聚苯乙烯珠 (PSB) 与免疫显性 HLA-A*02:01 限制性表位（肽-PSB）的混合物共价连接，这些表位可能在人类中具有高度的临床相关性，因为它们可以促进免疫耐受；然后我们研究了纳米颗粒-肽复合物对T细胞耐受性的影响。方法：通过静脉注射将HLA-A*02:01限制性表位的PSB偶联混合物给予HHD II小鼠。在NOD.β2mnullHHD小鼠中验证了其延缓病程的作用。在 1 型糖尿病个体中验证了致糖尿病 HLA-A*02:01 限制性细胞毒性淋巴细胞 (CTL) 对肽-PSB 治疗的反应。结果：我们表明肽-PSB 可以在 HHD II 小鼠中诱导抗原特异性耐受。保护性免疫机制是通过CD4+CD25+调节性T细胞的功能、抑制性T细胞活化和T细胞无反应性来介导的。此外，肽-PSB通过快速产生CD169+巨噬细胞衍生的C-C基序趋化因子22（CCL22）来诱导调节性T细胞和CD11c+树突状细胞的激活和积累。肽-PSB 还可以预防“人源化”NOD.β2mnullHHD 小鼠的糖尿病，并抑制 1 型糖尿病患者的致病性 CTL 反应。结论/解释：我们的研究结果首次证明了使用多肽-PSB 复合物诱导 T 细胞耐受并停止自身免疫过程的潜力。这些发现为 1 型糖尿病的抗原特异性耐受策略提供了一个有前途的平台，并强调了嗜金属巨噬细胞介导肽-PSB 诱导的免疫耐受所需的早期细胞间相互作用的机制。
Aims/hypothesis:Induction of antigen-specific immunological tolerance may provide an attractive immunotherapy in the NOD mouse model but the conditions that lead to the successful translation to human type 1 diabetes are limited. In this study, we covalently linked 500 nm carboxylated polystyrene beads (PSB) with a mixture of immunodominant HLA-A*02:01-restricted epitopes (peptides-PSB) that may have high clinical relevance in humans as they promote immune tolerance; we then investigated the effect of the nanoparticle-peptide complexes on T cell tolerance.Methods:PSB-coupled mixtures of HLA-A*02:01-restricted epitopes were administered to HHD II mice via intravenous injection. The effects on delaying the course of the disease were verified in NOD.β2mnullHHD mice. The diabetogenic HLA-A*02:01-restricted cytotoxic lymphocyte (CTL) responses to treatment with peptides-PSB were validated in individuals with type 1 diabetes.Results:We showed that peptides-PSB could induce antigen-specific tolerance in HHD II mice. The protective immunological mechanisms were mediated through the function of CD4+CD25+regulatory T cells, suppressive T cell activation and T cell anergy. Furthermore, the peptides-PSB induced an activation and accumulation of regulatory T cells and CD11c+dendritic cells through a rapid production of CD169+macrophage-derived C-C motif chemokine 22 (CCL22). Peptides-PSB also prevented diabetes in 'humanised' NOD.β2mnullHHD mice and suppressed pathogenic CTL responses in people with type 1 diabetes.Conclusions/interpretation:Our findings demonstrate for the first time the potential for using multipeptide-PSB complexes to induce T cell tolerance and halt the autoimmune process. These findings represent a promising platform for an antigen-specific tolerance strategy in type 1 diabetes and highlight a mechanism through which metallophilic macrophages mediate the early cell-cell interactions required for peptides-PSB-induced immune tolerance.
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影响因子：
7.7
作者：
Niens M;Grier AE;Marron M;Kay TW;Greiner DL;Serreze DV
通讯作者：
Serreze DV
影响因子：
168.9
作者：
Wherrett, Diane K.;Bundy, Brian;Becker, Dorothy J.;DiMeglio, Linda A.;Gitelman, Stephen E.;Goland, Robin;Gottlieb, Peter A.;Greenbaum, Carla J.;Herold, Kevan C.;Marks, Jennifer B.;Monzavi, Roshanak;Moran, Antoinette;Orban, Tihamer;Palmer, Jerry P.;Raskin, Philip;Rodriguez, Henry;Schatz, Desmond;Wilson, Darrell M.;Krischer, Jeffrey P.;Skyler, Jay S.
通讯作者：
Skyler, Jay S.
影响因子：
1.3
作者：
U. Yamashita;E. Kuroda
通讯作者：
U. Yamashita;E. Kuroda
DOI：
10.1073/pnas.0932778100
发表时间：
2003-07-08
影响因子：
11.1
作者：
Lieberman, SM;Evans, AM;DiLorenzo, TP
通讯作者：
DiLorenzo, TP
影响因子：
16.2
作者：
通讯作者：
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